Government indicators project that the proportion of Americans aged 65 or older is expected to increased from 12% to 29% of the population by the year 2030. As the U.S. population ages, the incidence and prevalence of Alzheimer's Disease (AD) will increase. AD is a chronic progressive dementing illness, that eventually leads to complete disability requiring assistance with all activities of daily living. Currently with an estimated 4 million Americans afflicted with AD the total health care costs are currently more than $100 billion per year. Slowing the progression or delaying the age of onset as little is five years would save an estimated $50 billion each year. Thus, it is of paramount importance to identifying new therapeutic targets to treat, prevent or slow the progression of AD s this would improve the quality of life of AD patients and their families as well as save billions of dollars. The molecular mechanisms accounting for the chronic neurodegeneration in Alzheimer's disease (AD) is not known. However, accumulating evidence indicates that amyloid-beta (Abeta) may play a prominent role. The exact mechanism of Abeta neurotoxicity has yet to be elucidated, but it may involve both induction of cytokines and local inflammatory responses as well as enhancement of glutamate toxicity. Several recent studies have led to the hypothesis that the pathogenesis of AD may be related to a local neuroimmune response and emerging data indicates that Abeta activates glia which release a variety of cytokines which may contribute to the toxicity associated with Abeta. Despite the tantalizing observations that Abeta toxicity and AD may, in part, be due to a local neuro immune response, very little is known about the molecular mechanisms by which Abeta activates TNFalpha receptors to activate TNFalpha dependent death pathways which induces the propagation of local neuroimmune interactions that ultimately lead to the characteristic AD pathology. Accordingly we propose to study the role of reactive neuro-cytokines in Abeta neurotoxicity. We will rigorously evaluate and extend our preliminary results and provide further supporting evidence that Abeta neurotoxicity involves an interaction with TNFalpha receptors and TNFalpha dependent death pathways. It is anticipated that these discoveries will lead to novel therapeutic interventions that could potentially slow the progression of AD.